Energy/Environment Models: Relationship to Planning in Wisconsin, GDR, Rhone Alps

This report is a description and cross-regional comparison of the institutional structures and modeling methodologies of the three regions participating in the IIASA Research Program on Management of Regional Energy/Environment Systems. Descriptions are presented for the state of Wisconsin (USA), the German Democratic Republic, and the Rhone-Alpes Region (France), by specialists and policy makers from the respective regions. These descriptions demonstrate quite vividly the relationships between the institutional structure of a region and its use of models and planning tools

Entwicklung von Strukturmodellen für Hydroxy-Interkalierte Tonminerale zur quantitativen Rietveld-basierten Phasenanalyse von Böden

Chemische und physikalische Bodeneigenschaften werden entscheidend vom Tongehalt und der Zusammensetzung der Tonfraktion geprägt. Tonminerale pedogenen Ursprungs können dabei sehr komplex sein. Insbesondere unter sauren Bedingungen kann gelöstes Al in den Zwischenschichten quellfähiger 2:1 Tonminerale (Smectit, Vermiculit) durch die Bildung nicht austauschbarer Al-Polymere gebunden werden. So kann eine Reihe sogenannter Hydroxy-Interkalierter Minerale (HIM) entstehen. Gegenwärtig entziehen sich diese Phasen jedoch einer verlässlichen Quantifizierung mittels Röntgenbeugung und Rietveld-Analyse, da hierfür keine kristallografischen Strukturmodelle vorliegen. Ziel unseres Projektes ist daher die Entwicklung von Strukturmodellen für die quantitative Beschreibung pedogener HIM-Phasen, welche folgende Schritte umfasst: (1) Identifizierung wichtiger natürlich vorkommender HIM in Böden unterschiedlichen Verwitterungsgrades, (2) Abtrennung/Herstellung phasenreiner Proben zur Prüfung/Verbesserung des Strukturmodells, sowie (3) Überprüfung des Strukturmodells an natürlichen Proben (Phasengemischen). Die Identifizierung typischer HIM wurde anhand einer 120.000 Jahre alten Bodenchronosequenz (Franz-Josef Gletscher, Neuseeland) vorgenommen. Hierbei konnten diverse intermediäre Phasen wie z.B. Vermiculit, Chlorit und Chlorit-Hydroxy-Interkalierter Smectit identifiziert werden, weshalb Hydroxy-Interkalierter Smectit (HIS) als erstes zu erstellendes Strukturmodell ausgewählt wurde. Da sich HIM generell im gleichen Korngrößenbereich anderer Tonminerale befinden, bzw. mit diesen verwachsen sind, können sie nicht phasenrein abgetrennt werden, wie für den zweiten Schritt der Modellentwicklung notwendig. Aus diesem Grund wurde im Labor eine Probenserie von 7 HIS aus natürlichem Smectit (Bentonit von Milos, Griechenland) mit unterschiedlichem Grad der Al-Belegung (0-100%) hergestellt. Hierfür wurde zu 6 Teilproben 0,1 mol/L AlCl3 gegeben und mit 0,3 mol/L NaOH Lösung bis pH=5,5 titriert. Die Teilproben unterschieden sich anhand der Volumina 0,1 mol/L AlCl3 Lösung sowie den Reaktionszeiten. Eine siebte Teilprobe wurde nicht behandelt (0% Belegung). Alle Proben wurden mittels Multimethodeneinsatz charakterisiert. Der vorliegende Beitrag gibt einen Einblick in den Ablauf und die damit verbundenen Schwierigkeiten in der Entwicklung eines Strukturmodells für HIM, welche eine quantitative Beschreibung von Hydroxy-Interkalierten Tonmineralen in Böden zukünftig ermöglichen soll

Primary care management for optimized antithrombotic treatment [PICANT]: study protocol for a cluster-randomized controlled trial

Background: Antithrombotic treatment is a continuous therapy that is often performed in general practice and requires careful safety management. The aim of this study is to investigate whether a best practice model that applies major elements of case management, including patient education, can improve antithrombotic management in primary health care in terms of reducing major thromboembolic and bleeding events. Methods: This 24-month cluster-randomized trial will be performed in 690 adult patients from 46 practices. The trial intervention will be a complex intervention involving general practitioners, health care assistants and patients with an indication for oral anticoagulation. To assess adherence to medication and symptoms in patients, as well as to detect complications early, health care assistants will be trained in case management and will use the Coagulation-Monitoring-List (Co-MoL) to regularly monitor patients. Patients will receive information (leaflets and a video), treatment monitoring via the Co-MoL and be motivated to perform self-management. Patients in the control group will continue to receive treatment-as-usual from their general practitioners. The primary endpoint is the combined endpoint of all thromboembolic events requiring hospitalization, and all major bleeding complications. Secondary endpoints are mortality, hospitalization, strokes, major bleeding and thromboembolic complications, severe treatment interactions, the number of adverse events, quality of anticoagulation, health-related quality of life and costs. Further secondary objectives will be investigated to explain the mechanism by which the intervention is effective: patients' assessment of chronic illness care, self-reported adherence to medication, general practitioners' and health care assistants' knowledge, patients' knowledge and satisfaction with shared decision making. Practice recruitment is expected to take place between July and December 2012. Recruitment of eligible patients will start in July 2012. Assessment will occur at three time points: baseline (T0), follow-up after 12 (T1) and after 24 months (T2). Discussion: The efficacy and effectiveness of individual elements of the intervention, such as antithrombotic interventions, self-management concepts in orally anticoagulated patients and the methodological tool, case-management, have already been extensively demonstrated. This project foresees the combination of several proven instruments, as a result of which we expect to profit from a reduction in the major complications associated with antithrombotic treatment

Drug metabolizing enzyme activities versus genetic variances for drug of clinical pharmacogenomic relevance

Enzymes are critically important in the transportation, metabolism, and clearance of most therapeutic drugs used in clinical practice today. Many of these enzymes have significant genetic polymorphisms that affect the enzyme's rate kinetics. Regarding drug metabolism, specific polymorphisms to the cytochrome (CYP) P450 enzyme family are linked to phenotypes that describe reaction rates as "ultra", "intermediate", and "poor," as referenced to "extensive" metabolizers that are assigned to wildtype individuals. Activity scores is an alternate designation that provides more genotype-to-phenotype resolution. Understanding the relative change in enzyme activities or rate of clearance of specific drugs relative to an individual's genotypes is an important component in the interpretation of pharmacogenomic data for personalized medicine. Currently, the most relevant drug metabolizing enzymes are CYP 2D6, CYP 2C9, CYP 2C19, thiopurine methyltransferase (TPMT) and UDP-glucuronosyltransferase (UGT). Each of these enzymes is reactive to a host of different drug substrates. Pharmacogenomic tests that are in routine clinical practice include CYP 2C19 for clopidogrel, TPMT for thiopurine drugs, and UDP-1A1 for irinotecan. Other tests where there is considerable data but have not been widely implemented includes CYP 2C9 for warfarin, CYP 2D6 for tamoxifen and codeine, and CYP 2C19 for the proton pump inhibitors

Stimulation programs for pediatric drug research – do children really benefit?

Most drugs that are currently prescribed in pediatrics have not been tested in children. Pediatric drug studies are stimulated in the USA by the pediatric exclusivity provision under the Food and Drug Administration Modernization Act (FDAMA) that grants patent extensions when pediatric labeling is provided. We investigated the effectiveness of these programs in stimulating drug research in children, thereby increasing the evidence for safe and effective drug use in the pediatric population. All drugs granted pediatric exclusivity under the FDAMA were analyzed by studying the relevant summaries of medical and clinical pharmacology reviews of the pediatric studies or, if these were unavailable, the labeling information as provided by the manufacturer. A systematic search of the literature was performed to identify drug utilization patterns in children. From July 1998 to August 2006, 135 drug entities were granted pediatric exclusivity. Most frequent drug groups were anti-depressants and mood stabilizers, ACE inhibitors, lipid-lowering preparations, HIV antivirals, and non-steroidal anti-inflammatory and anti-rheumatic drugs. The distribution of the different drugs closely matched the distribution of these drugs over the adult market, and not the drug utilization by children

Treatment of depressive disorders in primary care - protocol of a multiple treatment systematic review of randomized controlled trials

Background: Several systematic reviews have summarized the evidence for specific treatments of primary care patients suffering from depression. However, it is not possible to answer the question how the available treatment options compare with each other as review methods differ. We aim to systematically review and compare the available evidence for the effectiveness of pharmacological, psychological, and combined treatments for patients with depressive disorders in primary care. Methods/Design: To be included, studies have to be randomized trials comparing antidepressant medication (tricyclic antidepressants, selective serotonin reuptake inhibitors (SSRIs), hypericum extracts, other agents) and/or psychological therapies (e.g. interpersonal psychotherapy, cognitive therapy, behavioural therapy, short dynamically-oriented psychotherapy) with another active therapy, placebo or sham intervention, routine care or no treatment in primary care patients in the acute phase of a depressive episode. Main outcome measure is response after completion of acute phase treatment. Eligible studies will be identified from available systematic reviews, from searches in electronic databases (Medline, Embase and Central), trial registers, and citation tracking. Two reviewers will independently extract study data and assess the risk of bias using the Cochrane Collaboration's corresponding tool. Meta-analyses (random effects model, inverse variance weighting) will be performed for direct comparisons of single interventions and for groups of similar interventions (e.g. SSRIs vs. tricyclics) and defined time-windows (up to 3 months and above). If possible, a global analysis of the relative effectiveness of treatments will be estimated from all available direct and indirect evidence that is present in a network of treatments and comparisons. Discussion: Practitioners do not only want to know whether there is evidence that a specific treatment is more effective than placebo, but also how the treatment options compare to each other. Therefore, we believe that a multiple treatment systematic review of primary-care based randomized controlled trials on the most important therapies against depression is timely

Coumarin anticoagulants and co-trimoxazole: avoid the combination rather than manage the interaction

OBJECTIVE: The objective of our study was to examine the management of the interaction between acenocoumarol or phenprocoumon and several antibiotics by anticoagulation clinics and to compare the consequences of this interaction on users of co-trimoxazole with those for users of other antibiotics. METHODS: A follow-up study was conducted at four anticoagulation clinics in The Netherlands. Data on measurements of the International Normalised Ratio (INR), application of a preventive dose reduction (PDR) of the coumarin anticoagulant, fever and time within or outside the therapeutic INR range were collected. RESULTS: The study cohort consisted of 326 subjects. A PDR was given more often to users of co-trimoxazole PDR than to users of other antibiotics. The PDR in co-trimoxazole users resulted in a significantly reduced risk of both moderate overanticoagulation (INR >4.5) and severe overanticoagulation (INR >6.0) compared with no PDR, with odds ratios (ORs) of 0.06 [95% confidence interval (CI): 0.01-0.51] and 0.09 (95% CI: 0.01-0.92), respectively. In co-trimoxazole users without PDR, the risk of overanticoagulation was significantly increased compared with users of other antibiotics. All co-trimoxazole users spent significantly more time under the therapeutic INR range during the first 6 weeks after the course than users of other antibiotics. CONCLUSION: PDR is effective in preventing overanticoagulation in co-trimoxazole users, but results in a significantly prolonged period of underanticoagulation after the course. Avoidance of concomitant use of co-trimoxazole with acenocoumarol or phenprocoumon seems to be a safer approach than management of the interaction between these drugs

Clinically relevant safety issues associated with St. John's wort product labels

<p>Abstract</p> <p>Background</p> <p>St. John's wort (SJW), used to treat depression, is popular in the USA, Canada, and parts of Europe. However, there are documented interactions between SJW and prescription medications including warfarin, cyclosporine, indinavir, and oral contraceptives. One source of information about these safety considerations is the product label. The aim of this study was to evaluate the clinically relevant safety information included on labeling in a nationally representative sample of SJW products from the USA.</p> <p>Methods</p> <p>Eight clinically relevant safety issues were identified: drug interactions (SJW-HIV medications, SJW-immunosupressants, SJW-oral contraceptives, and SJW-warfarin), contraindications (bipolar disorder), therapeutic duplication (antidepressants), and general considerations (phototoxicity and advice to consult a healthcare professional (HCP)). A list of SJW products was identified to assess their labels. Percentages and totals were used to present findings.</p> <p>Results</p> <p>Of the seventy-four products evaluated, no product label provided information for all 8 evaluation criteria. Three products (4.1%) provided information on 7 of the 8 criteria. Four products provided no safety information whatsoever. Percentage of products with label information was: SJW-HIV (8.1%), SJW-immunosupressants (5.4%), SJW-OCPs (8.1%), SJW-warfarin (5.4%), bipolar (1.4%), antidepressants (23.0%), phototoxicity (51.4%), and consult HCP (87.8%). Other safety-related information on labels included warnings about pregnancy (74.3%), lactation (64.9%), discontinue if adverse reaction (23.0%), and not for use in patients under 18 years old (13.5%). The average number of <it>a priori </it>safety issues included on a product label was 1.91 (range 0–8) for 23.9% completeness.</p> <p>Conclusion</p> <p>The vast majority of SJW products fail to adequately address clinically relevant safety issues on their labeling. A few products do provide an acceptable amount of information on clinically relevant safety issues which could enhance the quality of counseling by HCPs and health store clerks. HCPs and consumers may benefit if the FDA re-examined labeling requirements for dietary supplements.</p

Pharmacodynamics, pharmacokinetics, and safety of single-dose subcutaneous administration of selatogrel, a novel P2Y12 receptor antagonist, in patients with chronic coronary syndromes

Aims  To study the pharmacodynamics and pharmacokinetics of selatogrel, a novel P2Y12 receptor antagonist for subcutaneous administration, in patients with chronic coronary syndromes (CCS). Methods and results  In this double-blind, randomized study of 345 patients with CCS on background oral antiplatelet therapy, subcutaneous selatogrel (8 mg, n = 114; or 16 mg, n = 115) was compared with placebo (n = 116) (ClinicalTrials.gov: NCT03384966). Platelet aggregation was assessed over 24 h (VerifyNow assay) and 8 h (light transmittance aggregometry; LTA). Pharmacodynamic responders were defined as patients having P2Y12 reaction units (PRU) <100 at 30 min post-dose and lasting ≥3 h. At 30 min post-dose, 89% of patients were responders to selatogrel 8 mg, 90% to selatogrel 16 mg, and 16% to placebo (P < 0.0001). PRU values (mean ± standard deviation) were 10 ± 25 (8 mg), 4 ± 10 (16 mg), and 163 ± 73 (placebo) at 15 min and remained <100 up to 8 h for both doses, returning to pre-dose or near pre-dose levels by 24 h post-dose. LTA data showed similarly rapid and potent inhibition of platelet aggregation. Selatogrel plasma concentrations peaked ∼30 min post-dose. Selatogrel was safe and well-tolerated with transient dyspnoea occurring overall in 7% (16/229) of patients (95% confidence interval: 4–11%). Conclusions  Selatogrel was rapidly absorbed following subcutaneous administration in CCS patients, providing prompt, potent, and consistent platelet P2Y12 inhibition sustained for ≥8 h and reversible within 24 h. Further studies of subcutaneous selatogrel are warranted in clinical scenarios where rapid platelet inhibition is desirable